Plasmacytoid dendritic cells (PDC) represent a unique cell type that plays a critical role in both innate and adaptive immune responses. During viral infection, PDC secrete massive amounts of type I interferon (IFN), as well as present viral antigens and prime T cell responses. In addition to antiviral immunity, PDC have been implicated into many immunological phenomena, including tolerance to oral antigens and allografts, allergic inflammation, antitumor immunity and autoimmunity. In the latter case, PDC were proposed to either promote autoimmune disease through aberrant IFN secretion or counteract it by modulating T cell differentiation. Thus, the precise function of PDC in prolonged immune reactions such as autoimmunity remains to be elucidated. This task calls for the development of novel genetic approaches, such as systems for constitutive PDC lineage ablation. Our lab has recently identified transcription factor E2-2 as a critical regulator of PDC development in mice and humans. We propose to use conditional targeting of E2-2 as a tool for constitutive PDC ablation in the steady state. In Specific Aim 1, E2-2 conditional knockout mice will be characterized for the efficiency and specificity of PDC ablation, and for their IFN secretion capacity and antiviral immune responses. In Specific Aim 2, the resulting "PDC-less" mice will be used to probe the role of PDC in spontaneous animal models of autoimmune neural inflammation and of lupus-like autoimmunity. These studies would generate a novel experimental system for the study of PDC, and provide insights into the role of PDC in autoimmune diseases. PUBLIC HEALTH RELEVANCE: The study is aimed at the functional analysis of plasmacytoid dendritic cells (PDC), a unique immune cell type that plays a major role in antiviral immunity and other immune responses. The development of a novel genetic model for constitutive PDC ablation would facilitate the study of PDC function and provide insights into the role of PDC in autoimmune diseases such as multiple sclerosis and lupus.